Through an international collaboration involving more than twenty Institutions in the US and Europe, we completed the first genome-wide association scan (GWAS) for age-related macular degeneration (AMD). GWAS are designed to identify common variants implicated in common diseases, which are normally not covered by linkage studies (2). Known AMD susceptibility loci near complement factor H (CFH), age-related maculopathy susceptibility 2 (ARMS2), complement component2/complement factor B (C2/CFB), complement component 3 (C3), and complement factor I (CFI) were confirmed by this study. Other previously suggested susceptibility loci did not show significance with P<0.05. However, in some cases a trend was observed in the same direction as that of the published data. The three strongest signals were associated with loci in the synapsin III (SYN3)/tissue inhibitor of metalloproteinase 3 (TIMP3) region, the hepatic lipase (LIPC) and cholesteryl ester transfer protein (CETP) genes. The SYN3/TIMP3 susceptibility locus had been previously linked to AMD. It is a large intron in the SYN3 gene (involved in neurotransmission and synapse formation) that also contains the TIMP3 gene (involved in extracellular matrix degradation and implicated in early-onset maculopathy -Sorby's fundus dystrophy-). Two other strongest signals were identified near the hepatic lipase (LIPC) and cholesteryl ester transfer protein (CETP) genes, loci also associated with high-density lipoprotein cholesterol HDL-c levels in the blood. Other HDL-c-associated alleles were examined and lipoprotein lipase (LPL) and ATP-binding cassette sub-family member 1 (ABCA1) genes showed evidence of strong association with AMD. All four alleles are associated with decreased blood HDL-c. However, alleles near CEPT and LPL appear to increase the risk of AMD, while alleles near LIPC and ABCA1 seem to decrease the risk of AMD. Thus, blood HDL-c may not be an appropriate marker for its impact on the risk of AMD. The susceptibility loci identified in this study point to two molecular pathways that could be considered as therapeutic targets in AMD: HDL-c metabolism and systemic transport and extracellular matrix degradation. AMD is a raising public health concern because of the constant increase in the aging population. The identification of susceptibility variants associated with AMD may contribute to the prediction of individual risk of AMD. This, in association with the identification of molecular and cellular pathways involved in the pathogenesis of the disease can lead to better preventive and therapeutic interventions. The two ARMS2 variants del443ins54 and rs11200638 at 10q26 had been suggested to affect mRNA stability and/or HTRA1 mRNA expression, respectively. When we examined expression levels of ARMS2 and HTRA1 in human retina samples carrying these genetic variants we did not find any change in their steady-state expression levels, thus excluding any association between AMD susceptibility variants at 10q26 and either ARMS2 or HTRA1 expression regulation in the human retina (3). Fuchs's corneal dystrophy (FCD) is a progressive condition characterized by dysfunction of the corneal endothelium that leads to loss of corneal transparency and consequently reduced vision. This condition may be deteriorate after cataract or refractive surgery and accounts for a large proportion of referrals for corneal transplantation. The capacity to identify patients at risk of FCD will allow informed decisions about cataract or refractive surgery. Loci on chromosome 5, 9, 13, and 18 had been linked with common age-related FCD. However, no genetic variant in these loci had been associated with FCD. Thus, in collaboration with A Edwards, our GWAS identified loci contributing to typical age-related FCD and replicated the most significant observations in a second, independent group of subjects (1). We found that at least two regions of the transcription factor 4 gene (TCF4) on chromosome 18q21, that encodes a member of the E-protein family (E2-2), were associated independently with FCD. In collaboration with a group in Poland, we have completed a genetic association study of the reported diabetic retinopathy (DR) susceptibility variants in a clinically well-characterized case control cohort of 1,217 caucasian patients with type 2 diabetes. Twenty-six single nucleotide polymorphisms (SNPs) in candidate genes were evaluated. Early genetic analysis has delivered encouraging results. We are currently planning a GWAS for diabetic retinopathy susceptibility variants. Finally, we are determining cellular/functional changes associated with aging of the retina in order to understand their contribution to the onset of retinal degeneration. To discover aging-associated adaptations that may influence rod function, we have generated gene expression profiles of purified rod photoreceptors from mouse retina at young adult to early stages of aging (<12 month-old). We identified 375 genes that showed differential expression in rods from 5 and 12 month-old mouse retina compared to that of 1.5 month-old retina. With aging, there appear to be a progressive shift in cellular homeostasis that may underlie the functional decline observed in rod photoreceptors and contribute to a more permissive state for retinal degeneration.